Antimicrobial resistance of clinical bacterial isolates in China: current status and trends

Abstract Antimicrobial resistance surveillance systems have been established in China. Two representative national surveillance networks are the China Antimicrobial Surveillance Network (CHINET) and China Antimicrobial Resistance Surveillance System (CARSS), both of which were established in 2005. For all clinical isolates collected in both of these surveillance networks, the ratio of Gram-negative bacilli to Gram-positive cocci was approximately 7:3 during the past 18 years. Generally, Gram-negative bacilli have a higher antimicrobial resistance profile in China. The prevalence of ESBLs in Escherichia coli is as high as approximately 50%. Acinetobacter baumannii-calcoaceticus complex (ABC) has a high antimicrobial resistance profile, with a carbapenem resistance rate of approximately 66%. However, the prevalence of carbapenem-resistant ABC has also shown a decreasing trend from 2018 to 2022. The prevalence of vancomycin-resistant Enterococcus was low, and the prevalence of MRSA and carbapenem-resistant Pseudomonas aeruginosa showed decreasing trends from 2005 to 2022. CHINET surveillance data demonstrated that the prevalence of carbapenem-resistant Klebsiella pneumoniae showed a remarkable increasing trend from 2.9% (imipenem resistance) in 2005 to 25.0% in 2018, and then slightly decreased to 22.6% in 2022. The decreasing trends may reflect the antimicrobial stewardship efforts in China: a professional consensus on the rational clinical use of carbapenems was issued by the National Health Commission of China and was well implemented nationally; after that, the clinical use of carbapenems decreased slightly in China.


Introduction
Antimicrobial resistance (AMR) has become a major global threat not only to public health but also to the social economy. 1 In 2022, 13 ministries of China led by the National Health Commission jointly updated the National Action Plan for AMR Containment (2022-25).Surveillance of bacterial resistance, which is important for the clinical empirical and targeted treatment of infection, is regarded as one of the primary tasks in this national action plan for solving the AMR problem.In this review, the current status and trends of AMR from 2005 to 2022 among common clinical isolates in China are presented, and the mechanisms of resistance for some AMR isolates are reviewed.Most of the resistance data were obtained from the two national bacterial AMR surveillance networks in China: China Antimicrobial Surveillance Network (CHINET; https://www.chinets.com) and China Antimicrobial Resistance Surveillance System (CARSS; https://www.carss.cn).

AMR surveillance system in China
AMR surveillance systems have been well established in China, including at hospital, province and national levels.Hospital-level AMR surveillance is required as the main task of antimicrobial stewardship measures, as local AMR data are crucial for rational, empirical administration of antibiotics, especially in hospitalacquired infections.The surveillance data were required to be fed back to clinicians via the hospital intranet and booklet distribution every quarter or half of the year. 2 Province-level AMR surveillance has been established over the past 35 years.Each province-level network includes more than 10 hospitals from all regions in each province and releases an annual report of AMR data.The Shanghai Bacterial Resistance Surveillance Network was established in 1988 with the help of the WHO Western Pacific Region Office. 2 Two national surveillance networks for bacterial AMR, CHINET and CARSS, were established in 2005.CHINET was launched by Huashan Hospital, affiliated with Fudan University, and it expanded to 73 hospitals across 29 provinces, municipalities and autonomous regions by 2022, including 53 general hospitals and 20 children's hospitals, of which 57 were tertiary hospitals and 16 were secondary hospitals. 3The CHINET surveillance system is dedicated to helping clinicians better understand the current status and trends of AMR and correct inappropriate prescription behaviours, thus assisting experts in formulating relevant guidelines and consensus in China and other Asian countries.More than 20 guidelines or expert consensus statements have been published with reference to the CHINET data. 4 Only one clinical isolate of the same species was included per patient per year based on their personal identification code to avoid isolates duplication.According to a CHINET uniform protocol, antimicrobial susceptibility testing (AST) was performed using automated systems in every local lab separately, supplemented by a disc diffusion method for some antimicrobial agents not available in automated systems.Quality control and test results were interpreted according to CLSI breakpoints for all agents tested, except for tigecycline and colistin.Tigecycline MICs, for which CLSI criteria were not available, were interpreted using US FDA MIC breakpoints.Colistin MICs were interpreted using the MIC interpretive breakpoints for colistin.The methods were consistent in all participating hospitals, which were verified every year. 6The CARSS protocol of AST was the same with CHINET.

E. coli
According to CHINET, cefotaxime resistance rates in E. coli increased from 52.2% in 2005 to 63.2% in 2012 and then decreased gradually to 50% in 2022, while ceftazidime resistance rates peaked at 30.9% in 2011, and then decreased steadily to 22.4% Cefotaxime or ceftriaxone resistance may be considered a marker of ESBL-producing isolates for carbapenem-susceptible strains, as the bla CTX-M -positive isolates were all resistant to cefotaxime or ceftriaxone. 7Ciprofloxacin resistance rates decreased from 68% in 2005 to 56% in 2016.Still, they escalated to 66.4% in 2019, which was due to the CLSI changing the breakpoints of fluoroquinolones for Enterobacterales in January 2019.According to the breakpoint of ciprofloxacin resistance, the MIC of E. coli changed from ≥4 to ≥1 mg/L.

Review
Amikacin resistance rates decreased smoothly from 11.9% in 2005 to 2.2% in 2022, while gentamicin resistance rates were above 30% in the last 5 years, according to the CHINET network.Resistance rates to piperacillin/tazobactam and imipenem were low in E. coli, ranging from 4%-6% and 0.7%-2.0%,respectively (Figure 4).The major mechanism of carbapenem resistance in carbapenem-resistant E. coli (CREC) is the production of MBL, predominantly NDM-1 and NDM-5.Other carbapenemases detected in CREC include KPCs, IMP and OXA, which are less common in E. coli. 8,9The resistance rates of colistin and tigecycline in E. coli have fluctuated around 1.0% and 0.1%, respectively, over the recent 5 years. 6

K. pneumoniae
The cefotaxime resistance rate in K. pneumoniae decreased slightly from 52.3% in 2006 to 42.7% in 2022 and the piperacillin/tazobactam resistance rate peaked at 30.1% in 2018 but decreased slightly to 26.6% in 2022.The prevalence of carbapenem-resistant K. pneumoniae (CRKP) increased from 2.9% (imipenem resistance) in 2005 to 25.0% in 2018, while it decreased slightly to 22.6% in 2022 (Figure 5). 3 This primarily was attributed to the consensus issued by the National Health Commission on the rational application of carbapenems to strengthen the management of the clinical use of carbapenems in 2018.The prevalence of CRKP ranged from 0.8% to 28.1% in different provinces, with an average rate of 10% (showing an increase from 7.4% in 2016) in the CARSS surveillance in 2022 (Figure 6). 5 The production of carbapenemases, especially KPCs, is the main mechanism of carbapenem resistance in CRKP, and the bla KPC-2 genotype accounts for more than 70%. 9The ceftazidime/avibactam resistance rate in K. pneumoniae isolates has been as low as 6% in the last two years. 6The most common mechanism of carbapenem resistance in K. pneumoniae collected from children is KPC-2, but the prevalence of NDM, especially NDM-1, is higher than in adults in China. 10,11The dominant clone of CRKP is ST11, which usually carries multiple resistance genes via plasmids and causes nosocomial infection outbreaks. 12The spread of ST11 may have contributed to the increasing trend of multiple and even extensive drug resistance in K. pneumoniae since 2015. 2 The colistin resistance rates increased from 1.1% in 2018 to 5.0% in 2022, and tigecycline resistance fluctuated between 2.5% and 5.2% in the last 5 years (Figure 5). 3

P. aeruginosa
P. aeruginosa had a relatively low resistance profile and a trend of decreasing resistance to the commonly used antimicrobials.The amikacin resistance rates dropped significantly from 23.0% in 2005 to 3.3% in 2022.The ceftazidime, piperacillin/tazobactam and ciprofloxacin resistance rates also dropped to 14.3%, 11.7% and 15.0%, respectively, in 2022. 3Carbapenem-resistant P. aeruginosa (CRPA) ranged from 7.6% in the Ningxia autonomous region to 26% in Shanghai, with an average rate of 16.6% in CARSS in 2022, 5 while the prevalence of CRPA was 23.8% in CHINET in 2022. 3The most common mechanisms of CRPA are overexpression of the efflux pump MexAB-OprM and inactivation of the outer membrane protein. 13Of the CRPA isolates, 32% had a carbapenemase gene in China, with the most common type being bla KPC-2 (23%-40.4% among CRPA strains),  Review followed by bla VIM-2 . 14,15Among the KPC-producing P. aeruginosa isolates, 50.3% (76/151) were resistant to ceftazidime/avibactam. 15Resistance to ceftazidime/avibactam significantly decreased from 11.1% to 6.3%, and the resistance rate of colistin fluctuated around 0.5% in P. aeruginosa, according to CHINET 2018-22 (Figure 7). 3

ABC
Generally, the resistance rates of ABC against all the commonly used antimicrobials were very high and showed an increasing trend, except for amikacin, according to CHINET 2005-22 (Figure 8).Resistance to ampicillin/sulbactam, cefoperazone/sulbactam and amikacin was 69.8%, 52.1% and 51.1%, respectively, in CHINET 2022. 3 Imipenem resistance rates increased from 31% in 2005 to 74.5% in 2018 and decreased slightly to 65.8% in 2022.Carbapenem-resistant ABC (CRABC) varied among provinces, with the lowest prevalence of 23.3% in Qinghai Province to the highest of 71% in Henan Province, with an average of 53.4% according to the results of CARSS in 2022. 5Clonal group 2 isolates producing acquired oxacillinases (Ambler class D β-lactamases), especially OXA-23 carbapenemases, account for a large proportion of CRABC cases worldwide, while 99% of CRABC produce OXA-23 in China.Other carbapenemase resistance genes, such as bla OXA-24 , bla NDM-237 and bla NDM-58 , have also been observed worldwide. 16Polymyxin and tigecycline resistance rates fluctuate around 1% and 2%, respectively. 3

S. aureus
The prevalence of MRSA has shown a remarkable decreasing trend from 69.0% in 2005 to 28.7% in 2022, according to CHINET data.The prevalence of MRSA in adults aged ≥18 years decreased from 85.8% in 2005 to 29.1% in 2022, whereas that in children aged <18 years increased from 18.0% to 27.1% during the same period (Figure 9). 3 No MRSA isolate was resistant to vancomycin or linezolid, and resistance to sulfamethoxazole/trimethoprim was as low as 6.6%, while resistance to clindamycin was as high as 53% in CHINET 2022. 3 The decreasing prevalence of MRSA is related to the effective implementation of nosocomial infection control measures, such as hand hygiene and antimicrobial stewardship measures in clinical practice in China.ST239 has historically been the dominant lineage in hospital infections in mainland China, but since 2013 community-associated strains including ST59 have largely been replacing the previously dominant healthcare-associated ST239. 17It is not clear whether the clone replacement is related to the decreasing MRSA prevalence.However, the significant increase in MRSA prevalence in children is a cause for concern.The increasing trend in children may be related to the increasing number of ICU beds in children's hospitals or departments that usually have higher bacterial resistance rates, including the prevalence of MRSA; limited choices of antimicrobials for treatment compared with adults may also be related to the increasing trend of MRSA prevalence.Other factors including shorter bed-to-bed distance and more frequent invasive operations such as aspiration of sputum may also be related to the increasing MRSA prevalence in children.Further studies focused on the increasing prevalence of MRSA in children are required in the future.The average MRSA prevalence among different provinces was 28.9%, ranging from 16% in Liaoning Province to 44% in the Xizang Autonomous Region, according to CARSS surveillance in 2022 (Figure 10). 4

Enterococci
The prevalence of VRE was relatively low in China: <5% for E. faecium and <1% for E. faecalis in the CHINET surveillance from 2005 Review to 2022 (Figure 11). 3 In the CARSS surveillance, the mean VRE prevalence was 1.7% for E. faecium, ranging from 0% to 11.7% across different provinces. 5The prevalence of VRE is much lower than that reported in many other countries around the world.The low VRE prevalence may be partially related to the infrequent use of oral vancomycin preparations, which are not available in China.IV preparations are administered orally to treat Clostridioides difficile infections if needed.Avoparcin has never been approved for use in animals in China.Enterococci become resistant to vancomycin by acquiring genes that influence cell wall formation. 18The genotypes encoding resistance to glycopeptides include vanA-G, vanL and vanM, and the predominant type prevalent in China and worldwide is vanA. 19The vanM gene was initially identified in a vancomycin-resistant E. faecium clinical isolate

S. pneumoniae
In 2017, the prevalence of penicillin-non-susceptible S. pneumoniae (PNSP), including penicillin-resistant S. pneumoniae and penicillin-intermediate S. pneumoniae, was higher in children than in adults (13.5% versus 8.2%).However, the gap has been narrowed since, as the prevalence of PNSP has reduced to 5.5% in children, while it had decreased to 4.6% in adults in the CHINET surveillance 2022. 3More than 90% of S. pneumoniae isolates were resistant to erythromycin or clindamycin in both children and adults.Of the S. pneumoniae isolates, 4.1% were resistant to levofloxacin, and 2.1% to moxifloxacin in adults, and even lower resistance rates

Review
(less than 0.5%) were found in children. 3 Mutations in PBPs are the main mechanism underlying penicillin resistance in S. pneumoniae.In China, the most prevalent serotypes were 19A (20.9%) and 23F (20.3%) in children and 3 (21.7%)and 19F (11.8%) in adults. 21he main serotypes in CSF isolates were 23F and 19F. 22n general, Gram-negative bacterial clinical isolates are much more common than Gram-positive cocci, with a ratio of approximately 7:3, and Gram-negative bacilli have higher AMR profiles; therefore, the AMR of Gram-negative bacilli is a dominant problem in China.The prevalence of ESBLs in E. coli remains as high as 50%, and the prevalence of CRKP is currently approximately 25%. A. baumannii has the highest AMR profile, with a CRABC prevalence of approximately 66%.The prevalence of MRSA and AMR in P. aeruginosa showed a decreasing trend from 2005 to 2022, and the prevalence of VRE was low.
The present review was based on the data of CHINET and CRASS over the past 18 years but still had some limitations.The members of both surveillance networks were increasing during the surveillance period, which may somewhat affect the comparability of the annual AMR data.Although the AST followed the uniform protocol, the testing was carried out separately at local labs of the participating hospitals.There was a lack of statistical analysis to clarify the real significance of AMR trends.In the future, it is important to have close monitoring on changing trends of carbapenem-resistant organism surveillance including CRKP, CRABC and CRPA.The higher MRSA prevalence in children caught wide attention; studies to identify the potential causes would be helpful to control the increasing trends of resistance.
'CHINET Cloud,' an openaccess online information network station of AMR, releases the latest surveillance data annually (semi-annually since 2022).Patients, physicians and researchers can browse heat maps, bar charts and trend charts of various bacteria in different years.Thousands of users are registered on the CHINET Cloud.The CARSS is organized by the Expert Committee on Rational Use of Drugs of the National Health Commission of the People's Republic of China.By the year 2021, 1997 hospitals from 31 provinces and autonomous regions had participated, including 1411 tertiary and 586 secondary hospitals. 5In this review, the comparison of AMR status among different provinces for each of the major clinical isolates was based on the CARSS data.

Figure 1 .
Figure 1.Percentages of Gram-positive cocci and Gram-negative bacilli of clinical isolates in China (CHINET data).

Figure 3 .
Figure 3. Percentages of the top eight clinical isolates (CHINET data).

Figure 4 .Figure 5 .
Figure 4. Resistance profile of E. coli for six commonly used antimicrobials (CHINET data).The CLSI breakpoints of fluoroquinolones for Enterobacterales changed in January 2019

Figure 7 .
Figure 7. Resistance profile of P. aeruginosa for five commonly used antimicrobials (CHINET data).

Figure 8 .
Figure 8. Resistance profile of ABC for five commonly used antimicrobials (CHINET data).

Figure 10 .
Figure 10.Prevalence of MRSA among different provinces in China among different provinces in China in 2022 (CARSS).